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Alcohol-induced ketonemia is associated with lowering of blood glucose, downregulation of gluconeogenic genes, and depletion of hepatic glycogen in type 2 diabetic db/db mice.

Abstract：

:Alcoholic ketoacidosis and diabetic ketoacidosis are life-threatening complications that share the characteristic features of high anion gap metabolic acidosis. Ketoacidosis is attributed in part to the massive release of ketone bodies (e.g., β-hydroxybutyrate; βOHB) from the liver into the systemic circulation. To date, the impact of ethanol consumption on systemic ketone concentration, glycemic control, and hepatic gluconeogenesis and glycogenesis remains largely unknown, especially in the context of type 2 diabetes. In the present study, ethanol intake (36% ethanol- and 36% fat-derived calories) by type 2 diabetic db/db mice for 9 days resulted in significant decreases in weight gain (∼19.5% ↓) and caloric intake (∼30% ↓). This was accompanied by a transition from macrovesicular-to-microvesicular hepatic steatosis with a modest increase in hepatic TG (∼37% ↑). Importantly, ethanol increased systemic βOHB concentration (∼8-fold ↑) with significant decreases in blood glucose (∼4-fold ↓) and plasma insulin and HOMA-IR index (∼3-fold ↓). In addition, ethanol enhanced hepatic βOHB content (∼5-fold ↑) and hmgcs2 mRNA expression (∼3.7-fold ↑), downregulated key gluconeogenic mRNAs (e.g., Pcx, Pck1, and G6pc), and depleted hepatic glycogen (∼4-fold ↓). Furthermore, ethanol intake led to significant decreases in the mRNA/protein expression and allosteric activation of glycogen synthase (GS) in liver tissues regardless of changes in the phosphorylation of GS, GSK-3β, or Akt. Together, our findings suggest that ethanol-induced ketonemia may occur in concomitance with significant lowering of blood glucose concentration, which may be attributed to suppression of gluconeogenesis in the setting of glycogen depletion in type 2 diabetes.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Srinivasan MP,Shawky NM,Kaphalia BS,Thangaraju M,Segar L

doi

10.1016/j.bcp.2018.12.005

subject

Has Abstract

pub_date

2019-02-01 00:00:00

pages

46-61

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(18)30504-5

journal_volume

160

pub_type

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Alcohol-induced ketonemia is associated with lowering of blood glucose, downregulation of gluconeogenic genes, and depletion of hepatic glycogen in type 2 diabetic db/db mice.